A Nerve-Fibroblast Axis in Mammalian Lung Fibrosis.

Tissue fibrosis contributes to pathology in vital organs including the lung. Curative therapies are scant. Myofibroblasts, pivotal effector cells in tissue fibrosis, accumulate via incompletely understood interactions with their microenvironment. In an investigative platform grounded in experimental lung biology, we find that sympathetic innervation stimulates fibrotic remodeling via noradrenergic α1-adrenergic receptor engagement in myofibroblasts. We demonstrate the anti-fibrotic potential of targeted sympathetic denervation and pharmacological disruption of noradrenergic neurotransmitter functions mediated by α1-adrenoreceptors (α1-ARs). Using the α1-adrenoreceptor subtype D as a representative α1-AR, we discover direct noradrenergic input from sympathetic nerves to lung myofibroblasts utilizing established mouse models, genetic denervation, pharmacologic interventions, a newly invented transgenic mouse line, advanced tissue mimetics, and samples from patients with diverse forms of pulmonary fibrosis. The discovery of this previously unappreciated nerve-fibroblast axis in the lung demonstrates the crucial contribution of nerves to tissue repair and heralds a novel paradigm in fibrosis research.

A novel case report of isolated cardiac myxedematosus.

Background: Cardiac mucinous deposits are a rare entity only previously described in the setting of scleromyxedema, a disorder characterized by cutaneous and systemic mucin deposits, fibroblastic proliferation, and monoclonal gammopathies. Case summary: A 41-year-old woman was transferred to our hospital after a month-long hospitalization with worsening cardiogenic shock requiring ionotropic support. Cardiac magnetic resonance imaging revealed a left ventricular ejection fraction of 23%, prior right coronary artery infarct, full-thickness late gadolinium enhancement in the left ventricle basilar wall, global abnormal parametric mapping parameters of both native T1, T2, and extracellular volume, and severe biventricular dysfunction concerning for infiltrative cardiomyopathy. Endomyocardial biopsy demonstrated heavy deposits of interstitial mucin, confirmed by electron microscopy; a Congo red stain was negative for amyloid. She was treated with an aggressive decongestive strategy, oral guideline-directed medical therapy, and intravenous immunoglobulin (IVIg); she was discharged home off inotropic support. Subsequently, she had three additional hospitalizations for heart failure exacerbation in a span of 6 months, and her overall prognosis remains guarded. Discussion: We report a first known case of isolated cardiac myxedematosus associated with a severe systolic and diastolic cardiomyopathy. Our patient did not have any clinical evidence of systemic scleromyxedema or paraproteinemia, both of which have been reported in association with cardiac mucin deposits. Mucinosus has been described in patients with systemic lupus erythematous; however, cardiac deposits have not been reported. While IVIg has been used as a treatment in previously reported cases of cardiac scleromyxedema, its clinical benefit remains unclear in isolated cardiac myxedematosus.

Plasma collagen neoepitopes are associated with multiorgan disease in the ACCESS and GRADS sarcoidosis cohorts.

INTRODUCTION: The pathogenesis of sarcoidosis involves tissue remodelling mediated by the accumulation of abnormal extracellular matrix, which is partly the result of an imbalance in collagen synthesis, cross-linking and degradation. During this process, collagen fragments or neoepitopes, are released into the circulation. The significance of these circulating collagen neoepitopes in sarcoidosis remains unknown. METHODS: We employed plasma samples from patients with sarcoidosis enrolled in A Case Control Etiologic Study of Sarcoidosis (ACCESS) and Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS), and healthy control patients recruited from the Yale community. Plasma concentrations of type III and VI collagen degradation (C3M and C6M) and formation (PRO-C3 and PRO-C6) were quantified via neoepitope-specific competitive ELISA, and statistical associations were sought with clinical phenotypes. RESULTS: Relative to healthy controls, the plasma of both sarcoidosis cohorts was enriched for C3M and C6M, irrespective of corticosteroid use and disease duration. While circulating collagen neoepitopes were independent of Scadding stage, there was a significant association between multiorgan disease and PRO-C3, PRO-C6 and C3M in the ACCESS cohort; PRO-C3 and C6M displayed this property in GRADS. These findings were unrelated to plasma levels of interleukin-4 (IL-4), IL-5, IL-6, IL-9, IL-10 and IL-13. Moreover, PRO-C3 was associated with dermatological disease in both cohorts. DISCUSSION: In two well-characterised sarcoidosis cohorts, we discovered that the plasma is enriched for neoepitopes of collagen degradation (C3M and C6M). In multiorgan disease, there was an association with circulating neoepitopes of type III formation (PRO-C3), perhaps mediated by dermatological sarcoidosis. Further investigation in this arena has the potential to foster new insights into the pathogenic mechanisms of this complex disease.

Macular Degeneration Drug Prescribing Patterns After Step Therapy Introduction in Medicare Advantage.

Importance: In Medicare Advantage (MA), step therapy for physician-administered drugs is an approach to lowering drug spending. The impact of step therapy in MA on prescribing behavior and the magnitude of any changes has not been analyzed. Objective: To evaluate the impact of step therapy on macular degeneration drug prescribing patterns for 3 large MA insurers. Design, Setting, and Participants: This was a retrospective encounter-based analysis using 20% nationally representative MA outpatient and carrier encounter records for 2017 to 2019. Participants were MA beneficiaries who were 65 years or older and had received a macular degeneration drug administration. Macular degeneration drug administrations for beneficiaries of MA Aetna, Humana, and UnitedHealthcare (UHC) insurers were assessed. Humana implemented macular degeneration step therapy in 2019, setting bevacizumab as the plan-preferred drug, and aflibercept and ranibizumab as the plan-nonpreferred drugs. Aetna and UHC, which did not implement macular degeneration step therapy, served as the control group. Data analyses were performed from May 2024 to December 2024. Exposures: A macular degeneration drug administration subject to a step therapy policy. Main Outcome and Measures: A binary indicator of whether the drug administered was bevacizumab. Linear probability models and a difference-in-differences framework were used to quantify changes in prescribing patterns before and after the introduction of step therapy for MA insurers that did and did not implement step therapy. To empirically measure the impact of step therapy, the first administration of a treatment episode was assessed, followed by switching patterns. Results: A total of 18 331 MA beneficiaries, 21 683 treatment episodes, and 171 985 drug administrations were included across the control and treatment groups. The difference-in-differences regressions found a 7.8% (95% CI, 4.9%-10.7%; P < .001) greater probability of being prescribed bevacizumab for the first administration due to step therapy. The predicted probabilities of preferred-drug administration in the treatment group increased from 0.61 to 0.70 between the periods before and after step therapy implementation for the first administration. Step therapy was not significantly associated with an increased rate of medication switching (hazard ratio, 0.86; 95% CI, 0.71-1.06; P = .15). Conclusions and Relevance: The findings of this retrospective encounter-based analysis indicate that step therapy is associated with a greater probability of prescribing the plan-preferred drug for the first administration. The analysis failed to find a statistically significant greater rate of medication switching within a treatment episode. Step therapy changed macular degeneration prescribing patterns, but step therapy alone did not transition all administrations to the plan-preferred drug.

Trophectoderm biopsy is associated with lower risks of moderate to extreme prematurity and low birthweights: a national registry cohort study of singleton livebirths from frozen-thawed blastocyst transfers.

BACKGROUND: Trophectoderm biopsy has become the mainstay assisted reproductive technique performed for preimplantation genetic testing, accounting for 43.8% of embryo transfer cycles in the United States in 2019 alone. Despite its prevalence, data on the obstetric and perinatal outcomes post-trophectoderm biopsy remains sparse and mixed. OBJECTIVE: This study aimed to examine the risks of adverse perinatal outcomes in birthweights and prematurity after transfers of the vitrified-thawed blastocyst with trophectoderm biopsy for preimplantation genetic testing. STUDY DESIGN: This was a retrospective observational cohort study of 45,712 singleton livebirths resulting from autologous vitrified-thawed blastocyst transfer cycles with or without trophectoderm biopsy for preimplantation genetic testing, reported by participating member clinics to the Society for Assisted Reproductive Technology national registry between 2014 and 2017. Adverse perinatal outcomes of preterm births and low birthweights were analyzed. Multivariable regression analyses were performed to control for covariates. Comparing the trophectoderm biopsy (n=21,584) and no trophectoderm biopsy (n=24,128) groups, adjusted odds ratios were calculated for the outcomes of small-for-gestational-age, large-for-gestational-age, low birthweight <2500 g, very low birthweight <1500 g, extremely low birthweight <1000 g, late preterm births <37 weeks, moderate preterm births <34 weeks, and extremely preterm births <28 weeks. RESULTS: Women in the trophectoderm biopsy group were older and more likely to have prior pregnancies, deliveries, and a history of spontaneous abortions. Tobacco use, diminished ovarian reserve, and recurrent pregnancy loss were also more prevalent in the trophectoderm biopsy group. Trophectoderm biopsy was not associated with small-for-gestational-age (adjusted odds ratio, 0.97; 95% confidence interval, 0.85-1.12; P=.72) or large-for-gestational-age newborns (adjusted odds ratio, 1.10; 95% confidence interval, 0.99-1.22; P=.09). Risks of preterm births <37 weeks gestation were similar between the biopsy and nonbiopsy groups (adjusted odds ratio, 0.93; 95% confidence interval, 0.85-1.02; P=.11). Trophectoderm biopsy was associated with a significantly lower risk of low birthweight <2500 g (adjusted odds ratio, 0.80; 95% confidence interval, 0.70-0.92; P<.001), very low birthweight <1500 g (adjusted odds ratio, 0.62; 95% confidence interval, 0.46-0.83; P<.001), extremely low birthweight <1000 g (adjusted odds ratio, 0.48; 95% confidence interval, 0.31-0.74; P<.001), moderate preterm birth <34 weeks (adjusted odds ratio, 0.76; 95% confidence interval, 0.64-0.91; P=.003), and extreme preterm birth <28 weeks (adjusted odds ratio, 0.63; 95% confidence interval, 0.43-0.92; P=.02). CONCLUSION: Trophectoderm biopsy is not associated with increased risks of small-for-gestational-age, large-for-gestational-age, or late preterm birth. Risks of low birthweight, very low birthweight, and extremely low birthweight from moderate and extreme preterm births are lower after trophectoderm biopsy, possibly by selecting against confined placental mosaicism or inducing placental epigenetic changes, the mechanisms of which warrant further investigation.

Metastatic malignant struma ovarii to the pituitary presenting as a sellar mass and responding to total thyroidectomy with adjuvant radioactive iodine therapy.

Malignant struma ovarii (MSO) is a rare ovarian teratoma composed primarily of thyroid tissue. Common sites of metastasis include peritoneum, bone, liver, lung, gastrointestinal tract and omentum. We present a woman in her 50s with a history of remote oophorectomy presenting with hypopituitarism and a 2.7 cm sellar mass. Trans-sphenoidal surgery for presumed pituitary macroadenoma achieved near total resection and resultant pathology surprisingly showed ectopic thyroid tissue. The patient acquired her ovarian pathology report from Southeast Asia which showed struma ovarii of the left ovary. The pituitary mass was thus determined to be a metastatic lesion from MSO. She underwent total thyroidectomy and radioactive iodine ablation therapy with good initial response and no regrowth of the tissue or emergence of distant metastases after 5 years of annual follow-up. To our knowledge, this is the first reported case of MSO to the pituitary.

Co-occurring psychiatric disorders in young people with eating disorders: An multi-state and real-time analysis of real-world administrative data.

OBJECTIVE: We aimed to use real-world data to characterize the burden of psychiatric comorbidities in young people with eating disorders (EDs) relative to peers without EDs. METHOD: This retrospective cohort study used a large federated multi-national network of real-time electronic health records. Our cohort consisted of 124,575 people (14,524 people receiving their index, first-ever, ED diagnosis, compared to 110,051 peers without EDs initiating antidepressants). After 1:1 propensity score matching of the two cohorts by pre-existing demographic and clinical characteristics, we used multivariable logistic regression to compute the adjusted odds ratio (aOR) of psychiatric diagnoses arising in the year following the index event (either first ED diagnosis or first antidepressant script). RESULTS: Over 50% of people with EDs had prior psychiatric diagnoses in the year preceding the index EDs diagnosis, with mood disorders, generalized anxiety disorder (GAD), post-traumatic stress disorder (PTSD), specific phobia (SP), attention-deficit hyperactivity disorder (ADHD), and autism spectrum disorder (ASD) being the most common. Adjusted analyses showed higher odds for mood disorders (aOR = 1.20 [95% CI = 1.14-1.26]), GAD (aOR = 1.28 [1.21-1.35]), PTSD (aOR = 1.29 [1.18-1.40]), and SP (aOR = 1.45 [1.31-1.60]) in the EDs cohort compared to antidepressant-initiating peers without EDs, although rates of ADHD and ASD were similar in both cohorts. CONCLUSION: This large-scale real-time analysis of administrative data illustrates a high burden of co-occurring psychiatric disorders in people with EDs.

Discovery of optimal cell type classification marker genes from single cell RNA sequencing data.

The use of single cell/nucleus RNA sequencing (scRNA-seq) technologies that quantitively describe cell transcriptional phenotypes is revolutionizing our understanding of cell biology, leading to new insights in cell type identification, disease mechanisms, and drug development. The tremendous growth in scRNA-seq data has posed new challenges in efficiently characterizing data-driven cell types and identifying quantifiable marker genes for cell type classification. The use of machine learning and explainable artificial intelligence has emerged as an effective approach to study large-scale scRNA-seq data. NS-Forest is a random forest machine learning-based algorithm that aims to provide a scalable data-driven solution to identify minimum combinations of necessary and sufficient marker genes that capture cell type identity with maximum classification accuracy. Here, we describe the latest version, NS-Forest version 4.0 and its companion Python package (https://github.com/JCVenterInstitute/NSForest), with several enhancements to select marker gene combinations that exhibit highly selective expression patterns among closely related cell types and more efficiently perform marker gene selection for large-scale scRNA-seq data atlases with millions of cells. By modularizing the final decision tree step, NS-Forest v4.0 can be used to compare the performance of user-defined marker genes with the NS-Forest computationally-derived marker genes based on the decision tree classifiers. To quantify how well the identified markers exhibit the desired pattern of being exclusively expressed at high levels within their target cell types, we introduce the On-Target Fraction metric that ranges from 0 to 1, with a metric of 1 assigned to markers that are only expressed within their target cell types and not in cells of any other cell types. NS-Forest v4.0 outperforms previous versions on its ability to identify markers with higher On-Target Fraction values for closely related cell types and outperforms other marker gene selection approaches at classification with significantly higher F-beta scores when applied to datasets from three human organs - brain, kidney, and lung.

Plasma free hemoglobin is associated with LDH, AST, total bilirubin, reticulocyte count, and the hemolysis score in patients with sickle cell anemia.

Plasma free hemoglobin (PFH) is a direct biomarker for hemolysis that has been associated with clinical complications such as pulmonary hypertension and death in patients with sickle cell disease (SCD). We sought to characterize the relationship between PFH and more clinically available hemolytic markers including lactate dehydrogenase (LDH), aspartate aminotransferase (AST), bilirubin, reticulocyte percentage and to derive a composite hemolysis score derived from principal component analysis (PCA) of these biomarkers. In 68 adult patients (median age 31 years old, IQR 25-39) with HbSS or HbSß0-thalassemia enrolled in the IMPROVE II study, median PFH was elevated at 21.9 mg/dL (IQR 9.9-44.9 mg/dL). Using Pearson correlation analysis, PFH had a stronger relationship to LDH (R=0.699), AST (R=0.587), and total bilirubin (R=0.475), compared to reticulocyte count (R=0.316). The hemolysis score was significantly associated with PFH (R=0.677). When compared with other laboratory measures, PFH correlated with hemoglobin (R= -0.275) and HbS (R=0.277),but did not correlate with white blood cell count (WBC) or HbF. The hemolysis score was significantly associated with WBC (R=0.307), hemoglobin (R = -0.393), HbF (R=- 0.424), and HbS (R=0.423). This study confirms that the conventional hemolytic biomarkers LDH, AST, bilirubin, and reticulocyte percentage correlate with PFH. Additionally, the hemolysis score is a valid tool to measure hemolysis and that it may be a marker of global hemolysis as opposed to PFH, which quantifies intravascular hemolysis. Further studies will be needed to elucidate the role of PFH and intravascular hemolysis in the development of clinical complications of sickle cell disease.

Medicare Advantage plan characteristics associated with sorting their beneficiaries to providers that generate fewer avoidable hospital stays.

OBJECTIVE: To examine whether certain Medicare Advantage (MA) plan characteristics are associated with driving beneficiaries to providers that generate fewer avoidable hospital stays. DATA SOURCES: This paper primarily used 2018-2019 MA encounter data and traditional Medicare (TM) claims data for a nationally representative 20% sample of Medicare beneficiaries. STUDY DESIGN: For each plan design aspect-plan type, carrier, star rating, and network breadth-we estimated two adjusted Poisson regressions of avoidable hospital stays: one without clinician fixed effects and the other with. We calculated the difference between the coefficients to evaluate the extent to which patient sorting affected avoidable hospital stays relative to TM. DATA EXTRACTION METHODS: Our sample included Medicare beneficiaries 65 years and older who were continuously enrolled in either MA or TM during 2018-2019. Beneficiaries in our sample had one or more chronic, ambulatory care-sensitive conditions. PRINCIPAL FINDINGS: Patient sorting can be attributed to certain characteristics of plan design aspects. For plan type, HMOs account for 86%, with PPOs accounting for only 14%. For carriers, Humana and smaller carriers account for 89%. For star ratings, high-star contracts account for 94%, with other stars only accounting for 6%. By network design, narrow network plan-counties explained 20% of the patient sorting effect. CONCLUSIONS: While MA plans were found to be associated with driving beneficiaries to providers that generate fewer avoidable hospital stays, the effect is not homogeneous across the characteristics of MA plans. HMOs and high-star contracts are drivers of this MA phenomenon.

Myeloid neoplasms in inflammatory bowel disease: A case series and review of the literature.

Patients with inflammatory bowel disease (IBD) are exposed to chronic systemic inflammation and are at risk for secondary malignancies. Here we review the literature on the risk of myeloid neoplasms (MN) in IBD and present the disease profiles of patients at a single institution with IBD who later developed MN, comparing them to those in the literature. No IBD characteristic was found to associate with MN disease severity, including the previously-identified association between MNs and thiopurine exposure. Of the somatic mutations identified in out cohort's MN, mutations in TET2 were most prevalent, followed by FLT3-ITD, BCR-ABL, and NPM1 mutations.

Equivalent thrombotic risk with Warfarin, Dabigatran, or Enoxaparin after failure of initial direct oral anticoagulation (DOAC) therapy.

BACKGROUND: The direct oral anticoagulants (DOACs) are now commonly regarded as first line anticoagulants in most cases of venous thromboembolism (VTE). However, the optimal choice of subsequent anticoagulant in instances of first line DOAC failure is unclear. OBJECTIVES: To describe and compare outcomes with second line anticoagulants used after DOAC failure. METHODS: Patients seen at an urban hospital system for an episode of acute VTE initially treated with either apixaban or rivaroxaban who experienced a subsequent recurrent thrombosis while on anticoagulation (1st recurrent thrombosis) were included. RESULTS: In total, 166 patients after apixaban or rivaroxaban failure were included. Following DOAC failure (1st recurrent thrombosis), the subsequent anticoagulant was warfarin in 60 patients (36%), dabigatran in 42 patients (25%), and enoxaparin in 64 patients (39%). Enoxaparin was preferentially prescribed in patients with a malignancy-associated etiology for 1st recurrent thrombosis (p < 0.01). The median follow-up time in our cohort was 16 months. There was no difference in 2nd recurrent thrombosis-free survival (p = 0.72) or risk for major bleeding event (p = 0.30) among patients treated with dabigatran, warfarin, or enoxaparin. CONCLUSIONS: In this retrospective analysis of patients failing first line DOAC therapy, rates of 2nd recurrent thrombosis and bleeding did not differ among subsequently chosen anticoagulants. Our study provides evidence that the optimal 2nd anticoagulant is not clear, and the choice of 2nd anticoagulant should continue to balance patient preference, cost, and provider experience.

Filgrastim and infliximab biosimilar uptake in Medicare Advantage compared with Traditional Medicare, 2016-2019.

BACKGROUND: Medicare Advantage (MA) and Traditional Medicare face different financing structures and incentives and may implement different strategies to encourage biosimilar uptake. Strategies used by health insurers can influence biosimilar uptake, which can in turn promote savings to insurers and patients. OBJECTIVE: To compare filgrastim and infliximab biosimilar uptake between MA and Traditional Medicare from 2016 to 2019 and examine biosimilar uptake by different MA carriers and plan types (Health Maintenance Organization [HMO] or Preferred Provider Organization). METHODS: We use a 2016-2019 nationally representative random 20% sample of the carrier (physician) and outpatient paid claims for Traditional Medicare data and final-action carrier and outpatient records for MA data. We compare quarterly biosimilar uptake from 2016 to 2019 for the first 2 drugs with biosimilar competition: (1) filgrastim, (Neupogen, originator), and biosimilars tbo-filgrastim (GRANIX) and filgrastim-sndz (ZARXIO), and (2) infliximab (Remicade, originator), and biosimilars infliximab-dyyb (Inflectra) and infliximab-abda (Renflexis). RESULTS: From their introduction, there was consistently greater uptake of filgrastim and infliximab biosimilars in MA compared with Traditional Medicare. By Q4 2019, filgrastim biosimilar uptake was 7.6 percentage points higher in MA (80.3%) than Traditional Medicare (72.7%). By Q4 2019, infliximab biosimilar uptake was 28.7% and 15.4% in MA and Traditional Medicare, respectively. Kaiser HMO plans were primarily responsible for the higher uptake of biosimilars in MA; in Q4 2019, filgrastim and infliximab biosimilar uptake was 98.8% and 78.8%, respectively. CONCLUSIONS: Our findings suggest that filgrastim and infliximab biosimilar uptake is greater in MA compared with Traditional Medicare, which is driven in part by particularly high uptake of biosimilars in MA Kaiser HMO plans. This highlights the need for future work to examine specific strategies and levers employed by MA Kaiser HMO plans and other insurers to increase biosimilar uptake, which can lead to cost savings for physician-administered drugs.

Role of Patient Sorting in Avoidable Hospital Stays in Medicare Advantage vs Traditional Medicare.

Importance: Unlike traditional Medicare (TM), Medicare Advantage (MA) plans limit in-network care to a specific network of Medicare clinicians. MA plans thus play a role in sorting patients to a subset of clinicians. It is unknown whether the performance of physicians who treat MA and TM beneficiaries is different. Objective: To examine whether avoidable hospital stay differences between MA and TM can be explained by the primary care clinicians who treat MA and TM beneficiaries. Design, Setting, and Participants: This was a cross-sectional study of a nationally representative sample of MA and TM beneficiaries in 2019 with any of 5 chronic ambulatory care-sensitive conditions (ACSCs). The relative risk (RR) of avoidable hospital stays in MA compared with TM was estimated with inverse probability of treatment-weighted Poisson regression, both without and with clinician fixed effects. The degree to which the estimated MA vs TM difference could be explained by patient sorting was calculated by comparing the 2 RR estimates. Data were analyzed between February 2022 and April 2023. Exposure: Enrollment in MA. Main Outcome and Measures: Whether a beneficiary had avoidable hospital stays in 2019 due to any of the ACSCs. Avoidable hospital stays included both hospitalizations and observation stays. Results: The study sample comprised 1 323 481 MA beneficiaries (mean [SD] age, 75.4 [7.0] years; 56.9% women; 69.3% White) and 1 965 863 TM beneficiaries (mean [SD] age, 75.9 [7.4] years; 57.1% women; 82.5% White). When controlling for the primary care clinician, the RR of avoidable hospital stays in MA vs TM changed by 2.6 percentage points (95% CI, 1.72-3.50; P < .001), suggesting that compared with TM beneficiaries, MA beneficiaries saw clinicians with lower rates of avoidable hospital stays. This effect size was statistically significant to explain the 2% lower rate of avoidable hospital stays in MA than in TM. Conclusions and Relevance: In this cross-sectional study of MA and TM beneficiaries, the lower rate of avoidable hospital stays among MA beneficiaries than TM beneficiaries was attributable to MA beneficiaries visiting clinicians with lower rates of avoidable hospital stays. The patient sorting that occurs in MA plays a critical role in the lower rates of avoidable hospital stays compared with TM.

Leukotriene A4 hydrolase inhibition improves age-related cognitive decline via modulation of synaptic function.

Leukotrienes, a class of inflammatory bioactive lipids, are well studied in the periphery, but less is known of their importance in the brain. We identified that the enzyme leukotriene A4 hydrolase (LTA4H) is expressed in healthy mouse neurons, and inhibition of LTA4H in aged mice improves hippocampal dependent memory. Single-cell nuclear RNA sequencing of hippocampal neurons after inhibition reveals major changes to genes important for synaptic organization, structure, and activity. We propose that LTA4H inhibition may act to improve cognition by directly inhibiting the enzymatic activity in neurons, leading to improved synaptic function. In addition, LTA4H plasma levels are increased in both aging and Alzheimer's disease and correlated with cognitive impairment. These results identify a role for LTA4H in the brain, and we propose that LTA4H inhibition may be a promising therapeutic strategy to treat cognitive decline in aging related diseases.

Teaching antenatal hand expression: a feasibility study in an inner urban U.S. hospital.

BACKGROUND: Many women have low confidence in breastfeeding and have concerns regarding low milk volume or discomfort with breastfeeding. Antenatal hand expression may be an opportunity to help women feel more comfortable with breastfeeding and help promote exclusive breastfeeding. A study at a hospital in Philadelphia, Pennsylvania, U.S. assessed the feasibility of teaching antenatal hand expression at 39 weeks among socioeconomically disadvantaged populations, overall participant satisfaction and adoption of hand expression and breastfeeding. METHODS: From March 2020 to June 2021, women recruited at 34-39 weeks were taught to hand express, collect, and store colostrum. Starting from 39 weeks, participants were asked to practice hand expression 1-3 times / day until delivery, log their experiences, and store colostrum expressed. Women were contacted to encourage continued hand expression and answer any questions. Postpartum, a survey assessed satisfaction with hand expression and issues encountered. The survey also inquired about breastfeeding plans and barriers, and whether women were exclusively breastfeeding (defined as infants who received only breastmilk from the time of birth). Chart review of postpartum or well-baby visit notes determined whether women continued breastfeeding. RESULTS: Of the 29 participants, 72% (21/29) reported hand expressing at home, and no women reported contractions when hand expressing. Participants rated mean satisfaction of 8.1/10 (SD = 1.62) with antenatal hand expression, mean satisfaction of 9.4/10 (SD = 0.90) toward hand expression education, mean likelihood of 9.4/10 (SD = 1.24) recommending hand expression to others, and a mean score of 8.1/10 (SD = 1.69) on how helpful hand expression was in breastfeeding initiation. 90% (26/29) of women initiated breastfeeding after birth and 72% (21/29) exclusively breastfed on discharge, but only 11/29 (38%) continued exclusively breastfeeding when re-assessed 4-6 weeks postpartum. Barriers included maternal discomfort, low milk supply, and maternal or infant illness. CONCLUSIONS: This study suggests that women in an urban setting would be willing to practice antenatal hand expression. A larger and adequately powered study could be feasible to determine associations between antenatal hand expression and breastfeeding rates and confidence.

Novel Frizzled-specific antibody-based Wnt mimetics and Wnt superagonists selectively activate WNT/ß-catenin signaling in target tissues.

WNTs are essential factors for stem cell biology, embryonic development, and for maintaining homeostasis and tissue repair in adults. Difficulties in purifying WNTs and their lack of receptor selectivity have hampered research and regenerative medicine development. While breakthroughs in WNT mimetic development have overcome some of these difficulties, the tools developed so far are incomplete and mimetics alone are often not sufficient. Here, we developed a complete set of WNT mimetic molecules that cover all WNT/ß-catenin-activating Frizzleds (FZDs). We show that FZD1,2,7 stimulate salivary gland expansion in vivo and salivary gland organoid expansion. We further describe the discovery of a novel WNT-modulating platform that combines WNT and RSPO mimetics' effects into one molecule. This set of molecules supports better organoid expansion in various tissues. These WNT-activating platforms can be broadly applied to organoids, pluripotent stem cells, and in vivo research, and serve as bases for future therapeutic development.

Safety, tolerability, pharmacokinetics, and immunogenicity of an anti-SARS-CoV-2 monoclonal antibody HFB30132A after single dose intravenous administration in healthy Chinese subjects: a phase 1, randomized, double-blind, placebo-controlled study.

Objective: The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) still protracts worldwide. HFB30132A is an anti- SARS-CoV-2 monoclonal antibody purposely engineered for an extended half-life with neutralizing activity against majority of the virus variants identified so far. The aim of this study was to evaluate the safety, tolerability, pharmacokinetics (PK), and immunogenicity of HFB30132A in healthy Chinese subjects. Methods: A phase 1, randomized, double-blind, placebo-controlled, single ascending dose clinical trial was designed. Twenty subjects were enrolled to Cohort 1 (1,000 mg dose level, 10 subjects) or Cohort 2 (2,000 mg dose level, 10 subjects). Subjects in each cohort were assigned randomly to receive a single intravenous (IV) dose of HFB30132A or placebo at a ratio of 8:2. Safety was assessed in terms of treatment emergent adverse events (TEAEs), vital signs, physical examination, laboratory tests, and ECG findings. PK parameters were measured and calculated appropriately. Anti-drug antibody (ADA) test was performed to detect anti-HFB30132A antibodies. Results: All subjects completed the study. Overall, 13 (65%) of the 20 subjects experienced TEAEs. The most common TEAEs were laboratory abnormalities (12 subjects [60%]), gastrointestinal disorders (6 subjects [30%]), and dizziness (4 subjects [20%]). All TEAEs were Grade 1 or Grade 2 in severity based on the criteria of Common Terminology Criteria for Adverse Events (CTCAE). Serum exposure (Cmax, AUC0-t, AUC0-∞) of HFB30132A increased with ascending dose. After single dose of 1,000 mg and 2000 mg HFB30132A, the mean Cmax was 570.18 µg/mL and 898.65 µg/mL, the mean AUC0-t value was 644,749.42 h*µg/mL and 1,046,209.06 h*µg/mL, and the mean AUC0-∞ value was 806,127.47 h*µg/mL and 1,299,190.74 h*µg/mL, respectively. HFB30132A showed low clearance ranging from 1.38 to 1.59 mL/h, and a long terminal elimination half-life (t½) of 89-107 days. ADA test did not detect any anti-HFB30132A antibodies Conclusion: HFB30132A was safe and generally well-tolerated after single IV dose of 1,000 mg or 2000 mg in healthy Chinese adults. HFB30132A did not induce immunogenic response in this study. Our data support further clinical development of HFB30132A. Clinical Trial Registration: https://clinicaltrials.gov, identifier: NCT05275660.